Clues For Genetic Anticipation In Multiple Endocrine Neoplasia Type 1

Broek, Medard F M van den; Nesselrooij, Bernadette P.M. van; Pieterman, Carolina R. C.; Stuart, A. A. Verrijn; Ven, Annenienke C van de; Herder, Wouter W. de; Dekkers, Olaf M.; Drent, Madeleine L.; Havekes, Bas; Kerstens, Michiel N.; Bisschop, Peter H.; Valk, Gerlof D.

doi:10.1210/clinem/dgaa257

Cited by 8 publications

(5 citation statements)

References 34 publications

(34 reference statements)

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“…Consider patient-specific factors. The clustering of specific manifestations in MEN1 kindreds, differences in sex distribution of manifestations (eg, thymic NETs), and possible genetic anticipation in MEN1 kindreds [ 11 ] strengthens the argument for tailoring screening schedule to the individual.…”

Section: Where Do We Go From Here? a Patient-centered Evidence-based Approachmentioning

confidence: 99%

MEN1 Surveillance Guidelines: Time to (Re)Think?

Newey

Newell‐Price

2022

Journal of the Endocrine Society

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Clinical Practice Guidelines for patients with Multiple Endocrine Neoplasia type 1 (MEN1) recommend a variety of surveillance options. Given progress over the past decade in this area, it is timely to evaluate their ongoing utility. MEN1 is characterized by the development of synchronous or asynchronous tumors affecting a multitude of endocrine and non-endocrine tissues, resulting in premature morbidity and mortality, such that the rationale for undertaking surveillance screening in at-risk individuals appears robust. Current guidelines recommend an intensive regimen of clinical, biochemical and radiological surveillance commencing in early childhood for those with a clinical or genetic diagnosis of MEN1, with the aim of early tumor detection and treatment. Although it is tempting to assume that such screening results in patient benefits and improved outcomes, the lack of a strong evidence base for several aspects of MEN1 care, and the potential for iatrogenic harms related to screening tests or interventions of unproven benefit, make such assumptions potentially unsound. Furthermore, the psychological, as well as economic burdens of intensive screening remain largely unstudied. Although screening undoubtedly constitutes an important component of MEN1 patient care, this perspective aims to highlight some of the current uncertainties and challenges related to existing MEN1 guidelines with a particular focus on the role of screening for pre-symptomatic tumors. Looking forward, a screening approach that acknowledges these limitations and uncertainties and places the patient at the heart of the decision-making process, is advocated.

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Section: Where Do We Go From Here? a Patient-centered Evidence-based Approachmentioning

confidence: 99%

MEN1 Surveillance Guidelines: Time to (Re)Think?

Newey

Newell‐Price

2022

Journal of the Endocrine Society

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“…This is a phenomenon where the symptoms of the genetic disorder appear at an earlier age with each generation when this disorder is passed on to the next generation. It has been suggested that the genetic anticipation is a feature explaining the age-related penetrance of some MEN1 linked manifestations [ 32 , 33 ], such as GEP-NET, PHPT and bpNET [ 33 ]. The role and genetic mechanisms involved in possible genetic anticipation of MEN1-TNET in previous studies have been difficult to assess due to its low prevalence and small number of cases.…”

Section: Discussionmentioning

confidence: 99%

Thymic neuroendocrine tumors in patients with multiple endocrine neoplasia type 1

et al. 2022

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Objective MEN1 is associated with an increased risk of developing tumors in different endocrine organs. Neuroendocrine tumors of the thymus (TNETs) are very rare but often have an aggressive nature. We evaluated patients with MEN1 and TNET in three university hospitals in Finland. Design/Methods We evaluated patient records of 183 MEN1-patients from three university hospitals between the years 1985–2019 with TNETs. Thymus tumor specimens were classified according to the new WHO 2021 classification of TNET. We collected data on treatments and outcomes of these patients. Results There were six patients (3.3%) with MEN1 and TNET. Five of them had the same common gene mutation occurring in Finland. They originated from common ancestors encompassing two pairs of brothers from sequential generations. The mean age at presentation of TNET was 44.7 ± 11.9 years. TNET was classified as atypical carcinoid (AC) in five out of six patients. One patient had a largely necrotic main tumor with very few mitoses and another nodule with 25 mitoses per 2 mm2, qualifying for the 2021 WHO diagnosis of large cell neuroendocrine carcinoma (LCNEC). In our patients, the 5-year survival of the TNET patients was 62.5% and 10-year survival 31.3%. Conclusion In this study, TNETs were observed in one large MEN1 founder pedigree, where an anticipation-like earlier disease onset was observed in the most recent generation. TNET in MEN1 patients is an aggressive disease. The prognosis can be better by systematic screening. We also show that LCNEC can be associated with TNET in MEN1 patients.

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“…Some controversies around the use of total/partial parathyroidectomy and their timing still exist, as patients may experience other tumors, such as gastrointestinal, lung, thymic, etc., and pituitary neuroendocrine neoplasia, leading to a dramatic burden and a reduced quality of life [53,54]. Screening protocols start in the second decade of life, and MEN1-related pediatric PHP seems the most important gene-associated form of PHP [55][56][57]. MEN1, an autosomal dominant condition with a clinical onset before the age of 20, is not studied across generous published cohorts with respect to juvenile PHP, and we only have a limited amount of information so far on this specific matter [58][59][60].…”

Section: Genetic Considerationsmentioning

confidence: 99%

Pediatric Neuroendocrine Neoplasia of the Parathyroid Glands: Delving into Primary Hyperparathyroidism

Carsote,

Stanciu,

Popa

et al. 2023

Biomedicines

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Our objective was to overview the most recent data on primary hyperparathyroidism (PHP) in children and teenagers from a multidisciplinary perspective. Methods: narrative review based on full-length, English-language papers (from PubMed, between January 2020 and July 2023). Results: 48 papers (14 studies of ≥10 subjects/study, and 34 case reports/series of <10 patients/study). Study-sample-based analysis: except for one case–control study, all of the studies were retrospective, representing both multicenter (n = 5) and single-center (n = 7) studies, and cohort sizes varied from small (N = 10 to 19), to medium-sized (N = 23 to 36) and large (N = 63 to 83); in total, the reviewed studies covered 493 individuals with PHP. Case reports/series (n = 34, N = 41): the mean ages studied varied from 10.2 to 14 years in case reports, and the mean age was 17 years in case series. No clear female predominance was identified, unlike that observed in the adult population. Concerning the assessments, there were four major types of endpoints: imaging data collection, such as ultrasound, 99mTc Sestamibi, or dual-phase computed tomography (CT); gene testing/familial syndrome identification; preoperative findings; and exposure to surgical outcome/preoperative drugs, like cinacalcet, over a 2.2-year median (plus two case reports of denosumab used as an off-label calcium-lowering agent). Single-gland cases (representing 85% of sporadic cases and 19% of genetic PHP cases) showed 100% sensitivity for neck ultrasounds, with 98% concordance with 99mTc Sestamibi, as well as a 91% sensitivity for dual-phase CT, with 25% of the lesions being ectopic parathyroids (mostly mediastinal intra-thymic). Case reports included another 9/41 patients with ectopic parathyroid adenomas, 3/41 with parathyroid carcinomas, and 8/41 subjects with brown tumors. Genetic PHP (which has a prevalence of 5–26.9%) mostly involved MEN1, followed by CDC73, CASR, RET, and CDKN1B, as well as one case of VHL. Symptomatic PHP: 70–100% of all cases. Asymptomatic PHP: 60% of genetic PHP cases. Renal involvement: 10.5% of a cohort with genetic PHP, 71% of sporadic PHP cases; 50% (in a cohort with a mean age of 16.7), 29% (in a cohort with a mean age of 15.2); 0% (in infancy) to 50–62% (in teenagers). Bone anomalies: 83% of the children in one study and 62% of those in two other studies. Gastrointestinal issues: 40% of one cohort, but the data are heterogeneous. Cure rate through parathyroidectomy: 97–98%. Recurrent PHP: 2% of sporadic PHP cases and 38% of familial PHP cases. Hungry bone syndrome: maximum rate of 34–40%. Case reports identified another 7/41 subjects with the same post-parathyroidectomy condition; a potential connection with ectopic presentation or brown tumors is suggested, but there are limited data. Minimally invasive thoracoscopic approaches for ectopic tumors seemed safe. The current level of statistical evidence on pediatric PHP qualifies our study- and case-sample-based analysis (n = 48, N = 534) as one of the largest of its kind. Awareness of PHP is the key factor to benefit our young patients.

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Clues For Genetic Anticipation In Multiple Endocrine Neoplasia Type 1

Cited by 8 publications

References 34 publications

MEN1 Surveillance Guidelines: Time to (Re)Think?

MEN1 Surveillance Guidelines: Time to (Re)Think?

Thymic neuroendocrine tumors in patients with multiple endocrine neoplasia type 1

Pediatric Neuroendocrine Neoplasia of the Parathyroid Glands: Delving into Primary Hyperparathyroidism

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